Crystalline forms of lenalidomide

ABSTRACT

The present invention provides for novel co-crystals of lenalidomide. The present invention particularly provides for novel cocrystals of lenalidomide with Resorcinol, Methyl paraben and Saccharin. The present invention also provides for the processes for the production of cocrystals of lenalidomide with Resorcinol, Methyl paraben and Saccharin. The present invention further provides for processes for the preparation of crystalline anhydrous lenalidomide Form IV.

RELATED APPLICATION

This application is a divisional application of U.S. patent applicationSer. No. 16/832,112 filed Mar. 27, 2020, which is a National Stage ofInternational Application No. PCT/IB2018/057500 filed Sep. 27, 2018,which claims the benefit of IN Patent Application 201741034364 filedSep. 27, 2017, each of which is herein incorporated by reference in itsentirety for all purposes.

TECHNICAL FIELD

The present invention relates to polymorphic forms of Lenalidomide. Inparticular, the invention relates to co-crystals of lenalidomide andprocesses for the preparation thereof. This invention also relates toprocesses for the preparation of crystalline anhydrous lenalidomide.

BACKGROUND AND PRIOR ART OF THE DISCLOSURE

REVLIMID® (Lenalidomide), a thalidomide analogue, is an immunomodulatoryagent with antiangiogenic and antineoplastic properties. The chemicalname for Lenalidomide is is 3(4-amino-1-oxo1,3-dihydro-2H-isoindo1-2-yl) piperidine-2,6-dione which is havingmolecular Formula C₁₃H₁₃N₃O₃ and molecular weight 259.3 and itsstructural Formula is as follows,

Lenalidomide inhibits proliferation and induces apoptosis of certainhematopoietic tumor cells including multiple myeloma, mantle celllymphoma, and del (5q) myelodysplastic syndromes in vitro. Lenalidomidecauses a delay in tumor growth in some in vivo nonclinical hematopoietictumor models including multiple myeloma Immunomodulatory properties oflenalidomide include activation of T cells and natural killer (NK)cells, increased numbers of NKT cells, and inhibition ofpro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

Lenalidomide which was disclosed in U.S. Pat. No. 5,635,517.Lenalidomide, chemically 3(4-amino-1-oxo 1,3-dihydro-2H-isoindo1-2-yl)piperidine-2,6-dione.

Lenalidomide is known to exist in various solid-state forms.

U.S. Pat. No. 7,977,357 B2 discloses Form A as an unsolvated,crystalline material that can be obtained from non-aqueous solventsystems; Form B as a hemihydrated, crystalline material that can beobtained from various solvent systems; Form C as a hemisolvatedcrystalline material that can be obtained from solvents; Form D as acrystalline, solvated polymorph prepared from a mixture of acetonitrileand water; Form E as a dihydrated, crystalline material; Form F as anunsolvated, crystalline material that can be obtained from thedehydration of Form E. Form G as an unsolvated, crystalline materialthat can be obtained from slurrying forms B and E in a solvent such as,but not limited to, tetrahydrofuran (THF). Form H as a partiallyhydrated crystalline material that can be obtained by exposing Form E to0% relative humidity.

PCT publication WO/2010/061209 A1 discloses a crystalline form ofanhydrous lenalidomide.

PCT publication WO/2010/129636 A1 discloses a Crystalline Form I oflenalidomide which may be characterized by a PXRD pattern comprising oneor more characteristic peaks located at about 8.9, 25.9 and 27.5±0.2degrees 2-theta.

PCT publication WO/2010/056384 A1 discloses a solvate of lenalidomidewith N,N-dimethylformamide (DMF), and a solvate of lenalidomide withdimethylsulfoxide (DMSO). Dimethylformamide solvate of lenalidomide maybe characterized by XRPD pattern having characteristic peaks at about7.9, 8.5, 8.7, 12.1, 14.1, 14.5, 15.1, 15.8, 17.0, 17.9, 18.8, 19.6,21.6, 22.0, 22.8, 23.3, 24.0, 24.4, 25.4, 26.6, and 26.9, ±0.2 degrees2-theta. Dimethylsulfoxide solvate of lenalidomide may be characterizedby an XRPD pattern having peaks at about 7.7, 8.8, 14.0, 14.6, 15.5,15.9, 16.4, 17.4, 18.7, 19.5, 20.3, 21.0, 21.9, 22.3, 23.6, 24.6, 25.3,and 27.9, ±0.2 degrees 2-theta.

U.S. Pat. No. 8,420,672 B2 discloses a crystalline form of lenalidomidequarterhydrate (1:0.25). The crystalline form may be characterized by anXRPD pattern having peaks at about 12.1±0.2, 12.6±0.2, 13.4±0.2,18.9±0.2, 20.0±0.2, 23.9±0.2, 24.7±0.2, 25.8±0.2, and 28.6±0.2 degreesin two theta.

U.S. Pat. No. 9,108,945 B2 discloses a crystalline form of anhydrouslenalidomide having weight loss of up to 0.13% between 25 and 225° C. bythermogravimetric analysis. The crystalline form may be furthercharacterized by an XRPD pattern having peaks at about 10.175±0.2,11.269±0.2, 15.772±0.2, 16.277±0.2, 17.646±0.2, 20.099±0.2, 24.098±0.2,25.230±0.2, 25.987±0.2, 28.320±0.2, and 32.595±0.2 degrees 2θ.

U.S. Pat. No. 9,808,450 B2 discloses co-crystals of lenalidomide with acoformer; wherein the coformer is benzoic acid, glycolic acid, hippuricacid, magnesium bromide, sodium lauryl sulfate, vanillic acid, or zincchloride.

U.S. Pat. No. 9,540,341 B2 discloses co-crystals comprising Lenalidomideand a compound selected from Urea, or Gallic acid, or Propyl gallate, orOxalic acid, or Malonic acid, or Ammonium chloride, or DL-tartaric acid,or L-tartaric acid.

Chinese patent application CN105837556 A discloses co-crystal oflenalidomide with nicotinamide.

SUMMARY OF THE INVENTION

Aspects of the present application provides co-crystals of lenalidomideand safe, simpler & economical processes for the preparation thereof.Each step of the process disclosed herein are contemplated both in thecontext of the multistep sequences described and individually.

First aspect of the present invention provides crystalline Lenalidomideco-crystal of Formula V.

Wherein R is a co-former selected from Resorcinol or Methyl paraben orSaccharin.

Second aspect of the present invention provides the crystallineLenalidomide-Resorcinol co-crystal of Formula Va characterized by ¹H NMRwhich is in accordance with the FIG. 1.

Third aspect of the present invention provides the crystallineLenalidomide-Resorcinol co-crystal of Formula Va which is furthercharacterized by DSC having endotherm at around 200±3° C. and the DSCpattern in accordance with the FIG. 2.

Fourth aspect of the present invention provides the crystallineLenalidomide-Resorcinol co-crystal of Formula Va which is furthercharacterised by PXRD having the main 2-theta values 7.20±0.2,12.90±0.2, 14.50±0.2, 19.60±0.2 and the PXRD pattern in accordance withthe FIG. 3.

TABLE 1 Num. Gonio d Int I/Imax 1 7.0004 12.6171 274 22.8 2 10.89488.11422 53 4.4 3 12.7807 6.92086 1203 100.0 4 13.3526 6.62568 75 6.3 513.9854 6.32728 1093 90.8 6 14.2399 6.21477 322 26.8 7 14.8249 5.97082152 12.7 8 15.1968 5.82551 91 7.6 9 15.4538 5.72921 83 6.9 10 16.19045.47018 398 33.1 11 17.9586 4.93535 64 5.3 12 18.4611 4.80214 34 2.8 1319.4178 4.56765 301 25.0 14 20.2083 4.39073 38 3.2 15 21.5045 4.12891268 22.3 16 21.6828 4.09535 243 20.2 17 22.0361 4.03049 86 7.2 1823.3210 3.81125 48 4.0 19 24.1929 3.67584 54 4.5 20 24.7960 3.58778 34528.6 21 25.2979 3.51773 135 11.3 22 25.7618 3.45542 1200 99.7 23 26.14443.40571 108 9.0 24 26.6204 3.34589 282 23.4 25 27.8138 3.20498 59 4.9 2628.2636 3.15499 177 14.7 27 29.0616 3.07014 62 5.2 28 30.2935 2.94805 514.2 29 31.0125 2.88131 54 4.5 30 32.5655 2.74737 66 5.5 31 33.22862.69404 75 6.2 32 34.0164 2.63343 64 5.3 33 35.1282 2.55258 59 4.9 3436.2109 2.47871 38 3.1 35 37.1185 2.42016 26 2.2 36 38.0975 2.36019 887.3 37 38.5910 2.33113 54 4.5 38 40.5217 2.2244 34 2.8 39 41.8707 2.155836 3.0 40 42.8864 2.10707 35 2.9 41 44.0647 2.05342 48 4.0 42 45.33351.99886 42 3.5 43 46.1030 1.96727 32 2.7 44 46.5645 1.94884 37 3.1 4546.9624 1.93325 31 2.6

Fifth aspect of the present invention provides the process for thepreparation of crystalline Lenalidomide-Resorcinol co-crystal of FormulaVa.

comprising the following steps,

Reduction of the Nitro intermediate of Formula II

in a suitable solvent at a suitable temperature in presence of asuitable acid to obtain a salt of Formula I

in situ treatment with Resorcinol in a suitable solvent/s at a suitabletemperature,

to obtain crystalline Lenalidomide-Resorcinol co-crystal of Formula Va.

Further, the present invention relates to the process for thepreparation for crystalline Lenalidomide-Resorcinol co-crystal ofFormula Va comprising following steps,

(i) Reducing the compound of formula II using a suitable reagent inpresence and a suitable acid in a suitable solvent at a suitabletemperature to obtain a salt of Formula I

(ii) Adjusting the pH of the solution containing formula I using asuitable base to a suitable range

(iii) Adding suitable equivalents of coformer-resorcinol

(iv) Stirring the reaction mixture at a suitable temperature

(v) Filtering the reaction mixture at a suitable temperature

(vi) Washing the solid with a suitable solvent/solution

(vii) Drying the wet solid at a suitable temperature/vacuum to obtain anovel crystalline Lenalidomide-Resorcinol co-crystal of Formula Va.

Further, the invention encompasses the process for the preparation of anovel Lenalidomide-Resorcinol cocrystal of Formula Va consisting of thefollowing wherein,

In step (i) suitable reagent contains but not limited to Pd/C. Suitablesolvent is selected from aqueous or organic solvents.

Further, the suitable solvent system is selected from water or a mixtureof water and an organic solvent wherein the organic solvent is selectedfrom alcohol preferably but not limited to C₁-C₃ alcohol.

Further, in step (i), suitable acid is selected from MeSO₃H, p-TolSO₃H,HCl preferably but not limited to MeSO₃H.

Further, in step (i), suitable temperature is selected in the rangebetween 25 and 50° C. preferably between 25 and 30° C.

Further, in step (ii), suitable pH range is selected between 7 and 14preferably between 7 and 9.

Further, in step (iii), suitable equivalents are selected in the rangebetween 0.5 and 10 preferably between 1.5 and 5.0.

Further, in steps (iv) and (v), suitable temperature is selected in therange between 25 and 90° C., preferably between 25 and 70° C.

Further, in steps (vi), suitable solvent/solution is selected from wateror a solution of resorcinol in water.

Further, in steps (vii), suitable temperature is selected in the rangebetween 25 and 90° C., preferably between 45 and 60° C. Suitable vacuumis selected in the range between 500 and 720 mm Hg, preferably between600 and 720 mm Hg.

Sixth aspect of the present invention provides the crystallineLenalidomide-Methyl Paraben co-crystal of Formula Vb characterized by ¹HNMR which is in accordance with the FIG. 4.

Seventh aspect of the present invention provides the crystallineLenalidomide-Methyl Paraben co-crystal of Formula Vb which is furthercharacterized by DSC having endotherm at around 120±5° C. and the DSCpattern in accordance with the FIG. 5.

Eighth aspect of the present invention provides the crystallineLenalidomide-Methyl Paraben co-crystal of Formula Vb which is furthercharacterised by PXRD having the main 2-theta values 17.12±0.2,18.69±0.2, 19.15±0.2, 21.47±0.2, 22.54±0.2, 25.27±0.2, 26.37±0.2,27.69±0.2 and the PXRD pattern in accordance with the FIG. 6.

TABLE 2 Num. Gonio d Int I/Imax 1 9.2056 9.599 55 5.4 2 9.6345 9.1726645 4.4 3 10.0474 8.79659 62 6.2 4 10.6316 8.31451 72 7.1 5 11.82647.47706 104 10.3 6 12.4323 7.11399 68 6.8 7 12.6703 6.98088 59 5.9 814.1051 6.27383 165 16.3 9 14.9919 5.90465 97 9.6 10 15.3121 5.78191 747.3 11 15.5714 5.68619 84 8.3 12 16.1294 5.49073 144 14.2 13 16.84725.25836 161 15.9 14 17.1228 5.17434 271 26.8 15 17.4852 5.0679 89 8.8 1617.9896 4.92694 92 9.1 17 18.6896 4.74396 943 93.1 18 19.1530 4.63021294 29.1 19 20.1219 4.40937 129 12.7 20 21.4708 4.1353 490 48.4 2122.5416 3.94123 293 28.9 22 23.4301 3.79376 87 8.6 23 23.6728 3.7554 939.1 24 23.8909 3.72161 87 8.6 25 25.2742 3.52097 1013 100.0 26 26.19163.39969 213 21.0 27 26.3687 3.37725 279 27.6 28 27.6880 3.21925 238 23.529 28.2886 3.15226 91 9.0 30 28.5559 3.12335 69 6.9 31 25.3534 3.0402966 6.5 32 30.2932 2.94807 71 7.0 33 30.7061 2.90937 65 6.5 34 31.14812.86908 42 4.1 35 32.1250 2.78403 59 5.8 36 32.9823 2.71359 59 5.8 3733.8865 2.64322 54 5.3 38 36.0359 2.49028 52 5.2 39 36.3425 2.47003 979.5 40 36.5408 2.45708 120 11.8 41 36.9595 2.4302 56 5.5 43 37.82972.37627 68 6.7 43 42.8973 2.10656 47 4.6 44 45.6110 1.98734 36 3.5

Ninth aspect of the present invention provides the process for thepreparation of crystalline Lenalidomide-Methyl Paraben co-crystal ofFormula Vb comprising the following steps,

Reduction of the Nitro intermediate of Formula II,

in a suitable solvent at a suitable temperature to obtain lenalidomideof Formula I

in situ treatment with Methyl paraben in a suitable solvent/s at asuitable temperature,

to obtain crystalline Lenalidomide-Methyl paraben co-crystal of FormulaVb.

Further, the present invention relates to the process for thepreparation for crystalline Lenalidomide-Methyl paraben co-crystal ofFormula Vb comprising following steps,

(i) Reducing the compound of formula II using a suitable reagent in asuitable solvent at a suitable temperature to obtain a lenalidomide ofFormula I (in situ)

(ii) Adding suitable equivalents of coformer-Methyl Paraben

(iii) Stirring the reaction mixture at a suitable temperature

(iv) Filtering the reaction mixture at a suitable temperature

(v) Optionally washing the solid with a suitable solvent/solution

(vi) Drying the wet solid at a suitable temperature/vacuum to obtainnovel crystalline Lenalidomide-Methyl Paraben co-crystal of Formula Vb.

Further, the invention encompasses the process for the preparation ofnovel Lenalidomide-Methyl Paraben cocrystal of Formula Vb consisting ofthe following wherein,

In step (i) suitable reagent contains but not limited to Pd/C. Suitablesolvent is selected from aqueous or organic solvents.

Further, the suitable solvent is selected from N,N-Dimethylacetamide,N,N-Dimethylformamide etc preferably, N,N-Dimethylacetamide

Further, in step (iii), suitable temperature is selected in the rangebetween 25 and 85° C. preferably between 50 and 85° C., more preferablybetween 75 and 85° C.

Further, in step (ii), suitable equivalents are selected in the rangebetween 0.5 and 10 preferably between 2 and 5.0.

Further, in steps (iii) suitable temperature is selected in the rangebetween 25 and 90° C., preferably between 50 and 90° C.

Further, in step (iv) suitable temperature is selected in the rangebetween 25 and 50° C., preferably between 25 and 35° C.

Further, in steps (v), suitable solvent/solution is selected from wateror a solution of Methyl paraben in water.

Further, in steps (vi), suitable temperature is selected in the rangebetween 25 and 90° C., preferably between 45 and 80° C. Suitable vacuumis selected in the range between 500 and 720 mm Hg, preferably between600 and 720 mm Hg.

Tenth aspect of the present invention provides the crystallineLenalidomide-Saccharin co-crystal of Formula Vc is characterized by ¹HNMR which is in accordance with the FIG. 7.

Eleventh aspect of the present invention provides the crystallineLenalidomide-Saccharin co-crystal of Formula Vc which is furthercharacterized by DSC having endotherm at around 185±3° C. and the DSCpattern in accordance with the FIG. 8.

Twelfth aspect of the present invention provides the crystallineLenalidomide-Saccharin co-crystal of Formula Vc which is furthercharacterized by PXRD having the main 2-theta values 15.00±0.2,16.05±0.2, 19.14±0.2, 20.14±0.2, 22.53±0.2, 25.18±0.2, 25.79±0.2 and thePXRD pattern in accordance with the FIG. 9.

TABLE 3 Num. Gonio d Int I/Imax 1 9.5994 9.2061 171 13.0 2 10.62868.31685 140 10.6 3 11.8038 7.49131 208 15.8 4 12.6279 7.00422 96 7.3 513.7550 6.43273 49 3.7 6 14.9972 5.90258 349 26.5 7 15.5112 5.70815 1027.7 8 16.0524 5.51688 686 52.1 9 16.8357 5.26193 158 12.0 10 18.17734.87647 131 10.0 11 19.1405 4.6332 868 66.0 12 20.1460 4.40416 342 26.013 20.4278 4.34404 53 4.0 14 21.5780 4.11502 99 7.5 15 22.5326 3.94279552 41.9 16 22.8343 3.89138 255 19.4 17 23.6415 3.76031 158 12.0 1823.8930 3.72129 286 21.7 19 25.1771 3.53433 1316 100.0 20 25.78643.45218 320 24.3 21 26.4994 3.36089 118 9.0 22 27.4787 3.2433 145 11.123 28.0484 3.1787 110 8.3 24 28.3076 3.15018 141 10.7 25 28.8917 3.0878141 3.1 26 29.4711 3.02841 84 6.4 27 29.7091 3.00469 39 2.9 28 30.59962.91924 108 8.2 29 30.9480 2.88717 80 6.1 30 32.1237 2.78414 109 8.2 3133.8474 2.64619 115 8.7 32 34.3332 2.60985 40 3.0 33 35.0748 2.55635 957.2 34 36.0271 2.49093 60 4.6 35 36.6844 2.44779 36 2.7 36 37.24582.41218 33 2.5 37 37.9759 2.36746 33 2.5 38 38.4084 2.3418 41 3.1 3939.0248 2.30621 44 3.3 40 39.8935 2.25797 33 2.5 41 40.2564 2.23845 372.8 42 41.5502 2.17169 48 3.6

Thirteenth aspect of the present invention provides the process for thepreparation of crystalline Lenalidomide-Saccharin co-crystal of FormulaVc comprising the following steps,

Reduction of the Nitro intermediate of Formula II

in a suitable solvent at a suitable temperature to obtain lenalidomideof Formula I

in situ treating with Saccharin in a suitable solvent/s at a suitabletemperature,

to obtain crystalline Lenalidomide-Saccharin co-crystal of Formula Vc.

Further, the present invention relates to the process for thepreparation for crystalline Lenalidomide-Saccharin co-crystal of FormulaVc comprising following steps,

(i) Reducing the compound of formula II using a suitable reagent in asuitable solvent at a suitable temperature to obtain a lenalidomide ofFormula I (in situ)

(ii) Adding suitable equivalents of coformer-Saccharin

(iii) Stirring the reaction mixture at a suitable temperature

(iv) Adding a suitable anti-solvent

(v) Filtering the reaction mixture

(v) Washing the solid with a suitable solvent/solution

(vi) Drying the wet solid at a suitable temperature/vacuum to obtainnovel crystalline Lenalidomide-Saccharin co-crystal of Formula Vc.

Further, the invention encompasses the process for the preparation ofnovel Lenalidomide-Saccharin co-crystal of Formula Vc consisting of thefollowing wherein,

In step (i) suitable reagent contains but not limited to Pd/C. Suitablesolvent is selected from aqueous or organic solvents.

Further, the suitable solvent system is selected from an organic solventwherein the organic solvent is from N,N,Dimethyl acetamide and or C₁-C₃alcohol preferably but not limited to N,N,Dimethyl acetamide.

Further, in step (i), suitable temperature is selected in the rangebetween 25 and 70° C. preferably between 50 and 70° C.

Further, in step (ii), suitable equivalents are selected in the rangebetween 0.5 and 10 preferably between 2.5 and 5.0.

Further, in step (iii), suitable temperature is selected in the rangebetween 25 and 90° C., preferably between 25 and 70° C.

Further, in steps (iv), suitable solvent/solution is selected from C₁-C₃alcohol preferably Methanol.

Further, in steps (vi), suitable temperature is selected in the rangebetween 25 and 90° C., preferably between 45 and 70° C. Suitable vacuumis selected in the range between 500 and 720 mm Hg, preferably between600 and 720 mm Hg.

Fourteenth aspect of the present invention provides a process for thepreparation of crystalline anhydrous lenalidomide Form IV.

TABLE 4 Num. Gonio d Int I/Imax 1 10.4076 8.49297 275 27.8 2 11.60287.62064 373 37.6 3 12.4283 7.11626 166 16.7 4 13.5234 6.54239 61 6.2 514.7506 6.00072 280 28.2 6 15.7072 5.63734 91 9.2 7 16.6286 5.32699 28328.6 8 18.0102 4.92133 258 26.1 9 18.9238 4.68577 982 99.0 10 20.21434.38944 86 8.7 11 21.5686 4.11677 72 7.3 12 22.3480 3.97494 991 100.0 1323.0115 3.86181 56 5.7 14 23.4546 3.78984 255 25.8 15 25.1456 3.53868 666.7 16 26.3269 3.38252 178 18.0 17 27.1654 3.27998 90 9.1 18 27.37183.25572 96 9.7 19 28.0925 3.17382 227 22.9 20 29.5228 3.02322 55 5.5 2129.9057 2.98538 37 3.7 22 30.5404 2.92477 157 15.8 23 31.9175 2.80165107 10.8 24 32.6393 2.74132 32 3.3 25 33.7302 2.65511 93 9.4 26 34.85432.57201 31 3.1 27 35.7815 2.50746 97 9.7 28 36.5661 2.45544 54 5.5 2937.0498 2.42449 29 2.9 30 38.2674 2.3501 25 2.6 31 39.0169 2.30666 323.2 32 40.1831 2.24237 21 2.1 33 40.8022 2.20976 21 2.1 34 42.73922.11399 37 3.7 35 44.0699 2.05319 29 2.9 36 44.4227 2.0377 32 3.3 3745.7841 1.98023 44 4.5 38 48.1482 1.88837 24 2.4 39 49.4495 1.84168 202.0

Fifteenth aspect of the present invention provides a process for thepreparation of crystalline anhydrous lenalidomide Form IV using novelcrystalline forms of lenalidomide co-crystals wherein coformers areselected from resorcinol, Methyl paraben & Saccharin.

Sixteenth aspect of the present invention provides a process for thepreparation of crystalline anhydrous lenalidomide Form IV usinglenalidomide resorcinol co-crystal of Formula Va, comprising thefollowing steps,

-   -   i. Heating a slurry of lenalidomide resorcinol co-crystal of        Formula Va in a suitable first solvent to a suitable temperature

-   -    to obtain a clear solution.    -   ii. Cooling the reaction mass to a suitable temperature.    -   iii. Mixing the reaction mass with a suitable second solvent.    -   iv. Stirred at room temperature for a suitable period of time.    -   v. Isolating the crystalline anhydrous lenalidomide Form IV.

Further, the invention encompasses the process for the preparation ofcrystalline anhydrous lenalidomide Form IV consisting of the followingwherein,

In step (i) suitable first solvent is selected from N,N-Dimethylacetamide, N,N-Dimethyl formamide, N,N-Dimethyl sulfoxide or a mixturethereof.

Further, in step (i), suitable temperature is selected in the rangebetween 40 and 70° C. preferably between 50 and 60° C.

Further, in step (iii), suitable second solvent is selected frommethanol, ethanol, propanol or a mixture thereof.

Further, in step (iv), suitable temperature is selected from 1 to 4 h,preferably between 1.5 to 2 h.

Seventeenth aspect of the present invention provides a process for thepreparation of crystalline anhydrous lenalidomide Form IV usinglenalidomide Methyl Paraben co-crystal of Formula Vb, comprising thefollowing steps,

-   -   i. Heating a slurry of lenalidomide Methyl Paraben co-crystal of        Formula Vb in a suitable first solvent to a suitable temperature

-   -    to obtain a clear solution.    -   ii. Cooling the reaction mass to room temperature.    -   iii. Mixing the reaction mass with a suitable second solvent.    -   iv. Stirred at room temperature for a suitable period of time.    -   v. Isolating the crystalline anhydrous lenalidomide Form IV.

Further, the invention encompasses the process for the preparation ofcrystalline anhydrous lenalidomide Form IV consisting of the followingwherein,

In step (i) suitable first solvent is selected from N,N-Dimethylacetamide, N,N-Dimethyl formamide, N,N-Dimethyl sulfoxide or a mixturethereof.

Further, in step (i), suitable temperature is selected in the rangebetween 40 and 70° C. preferably between 50 and 60° C.

Further, in step (iii), suitable second solvent is selected frommethanol, ethanol, propanol or a mixture thereof.

Further, in step (iv), suitable temperature is selected from 1 to 4 h,preferably between 1.5 to 2 h.

Eighteenth aspect of the present invention provides a process for thepreparation of crystalline anhydrous lenalidomide Form IV usinglenalidomide Saccharin co-crystal of Formula Vc, comprising thefollowing steps,

-   -   i. Heating a slurry of lenalidomide Saccharin co-crystal of        Formula Vc in a suitable first solvent to a suitable temperature

-   -    to obtain a clear solution.    -   ii. Cooling the reaction mass to room temperature.    -   iii. Mixing the reaction mass with a suitable second solvent.    -   iv. Stirred at room temperature for a suitable period of time.    -   v. Isolating the crystalline anhydrous lenalidomide Form IV.

Further, the invention encompasses the process for the preparation ofcrystalline anhydrous lenalidomide Form IV consisting of the followingwherein,

In step (i) suitable first solvent is selected from N,N-Dimethylacetamide, N,N-Dimethyl formamide, N,N-Dimethyl sulfoxide or a mixturethereof.

Further, in step (i), suitable temperature is selected in the rangebetween 40 and 70° C. preferably between 50 and 60° C.

Further, in step (iii), suitable second solvent is selected frommethanol, ethanol, propanol or a mixture thereof.

Further, in step (iv), suitable temperature is selected from 1 to 4 h,preferably between 1.5 to 2 h.

Nineteenth aspect of the present invention provides a process for thepreparation of crystalline anhydrous lenalidomide Form IV comprising thefollowing steps,

Reduction of the Nitro intermediate of Formula II

in a suitable first solvent at a suitable temperature to obtainlenalidomide of Formula I

in situ treating with a coformer in at a suitable temperature,

to obtain Lenalidomide-co-crystal of Formula V (in situ).

[Wherein R is a coformer selected from resorcinol, methyl paraben &saccharin.]

Treating the Lenalidomide-co-crystal of Formula V (in situ) with asuitable second solvent at a suitable temperature, stirring for asuitable period of time to isolate crystalline anhydrous lenalidomideForm IV.

Further, the present invention relates to the process for thepreparation for crystalline anhydrous lenalidomide Form IV comprisingfollowing steps,

(i) Reducing the compound of formula II using a suitable reagent in asuitable solvent at a suitable temperature to obtain a lenalidomide ofFormula I (in situ)

(ii) Adding suitable equivalents of coformer [coformer selected fromResorcinol, Methyl paraben & Saccharin]

(iii) Stirring the reaction mixture at a suitable temperature to obtainlenalidomide cocrystal (in situ)

(iv) Treating the above lenalidomide cocrystal (in situ) with a secondsolvent

(v) Isolating the as obtained solid, washing

(vi) Drying the wet solid at a suitable temperature/vacuum to obtaincrystalline anhydrous lenalidomide Form IV.

Further, the invention encompasses the process for the preparation ofcrystalline anhydrous lenalidomide Form IV consisting of the followingwherein,

In step (i) suitable reagent contains but not limited to Pd/C. Suitablesolvent is selected from aqueous or organic solvents.

Further, the suitable solvent system is selected from water or anorganic solvent wherein the organic solvent is selected fromN,N-Dimethyl acetamide, N,N-Dimethyl formamide, N,N-Dimethyl sulfoxide.

Further, in step (i), suitable temperature is selected in the rangebetween 50 and 80° C. preferably between 60 and 70° C.

Further, in steps (iv), suitable second solvent is selected fromalcoholic solvents, preferably selected from C1-C4 alcohols.

Accordingly, the different crystalline Lenalidomide forms of the presentinvention are prepared and characterised by orthogonal analytical tools.

Characterization techniques:

FT-IR, DSC, 1H NMR and PXRD techniques were used for characterising theco-crystal. The infrared spectroscopy, presents a great quantity ofinformation about the chemical bonds and interaction. It is a fastanalysis method, non-destructive.

The Powder X-ray diffraction is one of the most used techniques todetermine different crystalline structures. This technique candistinguish the presence of a new crystallographic motif, which can be apolymorph or a co-crystal. It is a non-destructive method and presentsdiffractions patterns unique for each structure.

The differential scanning calorimetry is a characterization method basedon the heat of reaction involved in different thermal events. For thepharmaceutical industry, the DSC is mostly used to obtain melting pointsof the API and thus, determine its purity. For the co-crystal analysis,there is a clear difference between the melting point of the co-formerand the co-crystal itself.

Instrumental parameters:

The ¹H-NMR spectrum recorded in Bruker 400 MHz spectrometer usingDMSO-d6 as solvent and chemical shifts are reported in ppm downfieldfrom TMS.

DSC was performed on a Discovery DSC (TA instruments). About 3-5 mg ofsample placed in crimped aluminium sample pan to be positioned on autosampler. The temperature range was from 30-350 0 C@10 0 C/min. Sampleswere purged by a stream of nitrogen flowing at 50 mL/min.

Equilibrate: 30° C.

Ramp: 10° C./min

Range: 30° C.-350° C.

The FT-IR spectrum (Fourier transform R spectroscopy) was recorded usingthe Fisher Scientific (NICOLET-i550-FTIR), equipped with a KBr splitterand a DTGS KBr detector. The spectrum was recorded in the range of 4000cm−1 to 400 cm−1

The powder X-ray powder diffractogram (XRPD) was obtained by using theinstrument XRD BRUKER D8 ADVANCE, equipped with LYNXEYE detector with 40mA current intensity and 40 kV voltage.

The sample was arranged on a Si-Zero background Sample holder andanalysed using the following parameters:

-   -   Scanning range (°): 3.000 to 60.000    -   Step size (°): 0.03    -   Scan type: Locked coupled    -   Scanning mode: continuous    -   Count time per step (s): 0.5    -   Delay time (s): 0    -   Divergent slit: 0.300    -   Antiscatter slit: 0.300

Advantages of present invention:

An API can exist in a variety of solid state forms, which include:polymorphs; solvates; hydrates; salts; co-crystals and amorphous forms.Each form exhibits unique physiochemical properties that can profoundlyinfluence the bioavailability, stability, manufacturability and otherperformance characteristics of the Formulated API.

Crystalline forms when compared to the amorphous form often show desiredunique physical and/or biological characteristics which usuallycontributes in the manufacture or Formulation of the active compound, tothe purity levels and uniformity required for regulatory approval.Hence, it is desirable to provide the pharmaceutically active ingredientin a substantially pure, crystalline and stable form of API.

Furthermore, the provision of further crystalline forms of apharmaceutically useful compound offers an opportunity to improve theperformance profile of a pharmaceutical product. In particular, not allsolid forms of a pharmaceutically useful compound are equally suited fordevelopment of a pharmaceutical dosage form. It is therefore desirableto widen the reservoir of materials a Formulation scientist can selectfrom, such that he can design a new dosage form of a drug havingimproved characteristics.

In simple terms, Co-crystals are an important class of pharmaceuticalmaterials that can enhance solubility and dissolution by forming acrystal of a drug and other benign molecule or co-former with specificstoichiometric compositions.

According to Almarsson and Zaworotko the definition of pharmaceuticalco-crystals—co-crystals are those that are formed between an activepharmaceutical ingredient (API) and a co-crystal former (CF), which is asolid under ambient conditions, and is not limited to two components.The components of the crystal interact by hydrogen bond or othernoncovalent and non-ionic interactions (Ö. Almarsson, M. J. Zaworotko,“Crystal engineering of the composition of pharmaceutical phases. Dopharmaceutical co-crystals represent a new path to improved medicines?”Chem. Commun. 2004, 17, pp. 1889-1896).

Advantages of Novel Crystalline Lenalidomide-Resorcinol co-crystal:

-   -   Hygroscopicity is lesser or comparable with that of Lenalidomide        hemihydrate. Form-C experiences significant weight loss about        6.03% (U.S. Pat. No. 7,465,800 B2). However, novel        Lenalidomide-Resorcinol co-crystal does not exhibit significant        weight change.    -   Novel Lenalidomide-Resorcinol co-crystal is thermally stable        (neat, at least up to 80° C.).    -   Water slurry experiment has been performed to understand the        relative solubility wrt Lenalidomide hemihydrate. Accordingly,        Lenalidomide-Resorcinol co-crystal was slurried with water. PXRD        analysis of the sample after 1 day indicated the co-crystal has        been transformed to a different form indicating that it is more        soluble than the Lenalidomide hemihydrate.    -   Economical process of preparation.    -   The procedure involves in-situ synthesis of Lenalidomide        co-crystal formation without the isolation of Lenalidomide.    -   The process for the preparation of novel Lenalidomide-Resorcinol        co-crystal is scaleup friendly.    -   The process for the preparation of novel Lenalidomide-Resorcinol        co-crystal does not involve the necessity of inert condition.

Crystalline anhydrous lenalidomide Form IV:

This has been disclosed in Cryst. Growth, 2017, 17, 612-628. However,the process involves heating of Lenalidomide hemihydrate to a hightemperature to obtain Form IV.

The process has following disadvantages.

-   -   Not scale up friendly.    -   Specific temperature (140° C.) is necessary to obtain the        desired polymorph i.e. Form IV. Any change in the temperature        will result in different polymorphs.    -   Input is Lenalidomide hemihydrate.

Advantages of novel crystalline Lenalidomide-Saccharin co-crystal:

-   -   Saccharin is pharmaceutically acceptable and listed in FDA        Inactive Ingredients.    -   Saccharin Toxicity-Acute oral toxicity (LD₅₀): 17000 mg/kg        [Mouse])    -   Scale up friendly process.    -   Isolation crystalline Lenalidomide does not involve any        Lenalidomide in any forms such as anhydrous, hemihydrate or        dihydrate.

BRIEF DESCRIPTION OF THE FIGURES

In order that the disclosure may be readily understood and put intopractical effect, reference will now be made to exemplary embodiments asillustrated with reference to the accompanying figures. The figurestogether with a detailed description below, are incorporated in and formpart of the specification, and serve to further illustrate theembodiments and explain various principles and advantages, in accordancewith the present disclosure wherein:

FIG. 1: Illustrates the ¹H NMR pattern of the crystallineLenalidomide-Resorcinol co-crystal of Formula Va.

FIG. 2: Illustrates the DSC thermogram of the crystallineLenalidomide-Resorcinol co-crystal of Formula Va.

FIG. 3: Illustrates the PXRD of crystalline Lenalidomide-Resorcinolco-crystal of Formula Va.

FIG. 4: Illustrates the ¹H NMR pattern of the crystallineLenalidomide-Methyl Paraben co-crystal of Formula Vb.

FIG. 5: Illustrates the DSC thermogram of the crystallineLenalidomide-Methyl Paraben co-crystal of Formula Vb.

FIG. 6: Illustrates the PXRD of the crystalline Lenalidomide-MethylParaben co-crystal of Formula Vb.

FIG. 7: Illustrates the ¹H NMR pattern of the crystallineLenalidomide-Saccharin co-crystal of Formula Vc.

FIG. 8: Illustrates the DSC thermogram of the crystallineLenalidomide-Saccharin co-crystal of Formula Vc.

FIG. 9: Illustrates the PXRD of the crystalline Lenalidomide-Saccharinco-crystal of Formula Vc.

FIG. 10: Illustrates the PXRD of the crystalline anhydrous lenalidomideForm IV.

The method of analysis of the compounds represented in the figures asabove are as below:

PXRD Analysis

About 300 mg of powder sample was taken onto the sample holder and wastightly packed on the sample holder uniformly by means of glass slideand Powder X-ray diffraction was recorded on Bruker D8 Advancediffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Kα X-radiation(λ=1.5406 Å) at 40 kV and 30 mA powder. X-ray diffraction patterns werecollected over the 2θ range 3-50° at a scan rate of 1°/min.

DSC Analysis

DSC was performed on a Mettler Toledo DSC 822e module. 4-6 mg of samplewas placed in crimped but vented aluminium sample pans. The temperaturerange was from 30-250° C.@10° C./min. Samples were purged by a stream ofnitrogen flowing at 80 mL/min.

IR Analysis

IR was performed on a Fisher Scientific (NICOLET-iS50-FTIR). About 5 mgof sample was spread over the region of diamond ATR sampling station andcollected the sample spectrum between 4000 cm−1 to 400 cm−1 to obtain aspectrum of suitable intensity (above 60% transmission at 2000 cm−1).

DETAILED DESCRIPTION OF THE INVENTION

The embodiments of the present invention are further described usingspecific examples herein after. The examples are provided for betterunderstanding of certain embodiments of the invention and not, in anymanner, to limit the scope thereof. Possible modifications andequivalents apparent to those skilled in the art using the teachings ofthe present description and the general art in the field of theinvention shall also form the part of this specification and areintended to be included within the scope of it.

Schemes

General Example-1

To a hydrogenator were added Formula II, a suitable solvent and ahydrogenation catalyst. The reaction mass was stirred under H₂atmosphere at a suitable temperature for a suitable amount of time.After completion of the reaction the reaction mass was cooled, filteredand the product as obtained in solution is subjected to charcoalisationfollowed by treatment with a suitable coformer R [wherein R is selectedfrom Resorcinol, Methyl Paraben & Saccharin], stirred at a suitabletemperature for a suitable amount of time and isolated crystallinelenalidomide cocrystal of Formula V. The crystalline lenalidomidecocrystal of Formula V was dissolved in a suitable first solvent, heatedto a suitable temperature and cooled to a suitable temperature followedby addition of a second solvent. The reaction mass was stirred for asuitable duration and isolated crystalline anhydrous lenalidomide FormIV.

As explained above the crystalline anhydrous lenalidomide Form IV isconveniently prepared using any of the coformers selected fromResorcinol, Methyl Paraben & Saccharin.

Example 1a: [Using Crystalline Lenalidomide Saccharin Cocrystal]

Step-A:

To a suspension of Formula-II (50.0 g, 0.173 mol) in N,N-Dimethylacetamide (250 mL, 5.0 vol.), 10% Pd/C (5.0 g, 0.1% w/w) was added intoa hydrogenator. The mass was stiffed at 25±5° C. under H₂ gas (90 psi)atmosphere. After completion of the reaction (Monitored through HPLC),the mass was filtered through celite, washed with N,N-Dimethyl acetamide(100 mL, 2.0 vol). The resulting filtrate subjected for Charcoal (5.0 g,0.1% w/w) treatment, filtered through celite bed at 55±5° C., washedwith N,N-Dimethyl acetamide (100 mL, 2.0 vol) to obtain Formula-I as asolution in DMAc (480 g).

Step-B:

To a solution of Formula-I in N,N-Dimethyl acetamide (480 g, 0.166 mol,Obtained from Step-A), Formula-IIIc (106.6 g, 0.582 mol) was added. Themass was concentrated under reduced pressure to a syrupy mass. It wascontacted with MeOH (431 mL, 10.0 vol) at 25±5° C., filtered, and driedunder reduced pressure at 55±5° C. to obtain a Formula-Vc as an offwhite solid (71.0 g).

Step-C:

A mixture of Formula-Vc (20.0 g, 0.032 mol) in N,N-Dimethyl acetamide(80.0 mL, 4.0 vol) was heated to 45-50° C., cooled to 25-30° C. Methanol(200 mL, 10.0 vol) was added and the solid formed was filtered and driedat 80° C. under vacuum to obtain a Formula-I as an off-white solid.

General Example-2

To a hydrogenator were added the Formula II, a suitable solvent and ahydrogenation catalyst. The reaction was stirred under H₂ atmosphere ata suitable temperature for a suitable amount of time. After completionof the reaction the reaction mass was cooled, filtered and the productas obtained in solution is subjected to charcoalisation. Thecharcoalised solution is treated with a suitable coformer R [wherein Ris selected from Resorcinol, Methyl Paraben & Saccharin], stirred at asuitable temperature for a suitable amount of time and the lenalidomidecocrystal of Formula V as obtained was taken to next step withoutisolation. The solution of lenalidomide cocrystal of Formula V is heatedto a suitable temperature and cooled to room temperature followed byaddition of a second solvent. The reaction mass was stirred for asuitable duration and isolated crystalline anhydrous lenalidomide FormIV.

As explained above the crystalline anhydrous lenalidomide Form IV isconveniently prepared using any of the coformers selected fromResorcinol, Methyl Paraben & Saccharin.

Example-2a Step-a:

To a suspension of Formula-II (100 g, 0.345 mol.) in N,N-Dimethylacetamide (500 mL, 5.0 vol.) was added 10% Pd/C (10.0 g, 0.1% w/w) intoa hydrogenator. This reaction mass was stirred at 60±5° C. under H2atmosphere for 3 h. After completion of the reaction indicated by theHPLC, mass was cooled to 25±5° C., filtered through Celite® bed, washedwith N,N-Dimethyl acetamide (200 mL, 2.0 vol.). Filtrate was transferredinto a reactor, charcoalised and the mass was filtered through Celite®bed at 45±5° C., washed with N,N-Dimethyl acetamide (200 mL, 2.0 vol.)to obtain Formula-I in DMAc as a yellow colour solution.

Step-b:

To a solution of Formula-I in N,N-Dimethyl acetamide (0.194 mol.obtained as in step-a) was contacted with saccharin as coformer ofFormula-IIIc (125.67 g, 0.686 mol.). This mass was concentrated underreduced pressure to obtain a syrupy mass (Formula-Vc). This mass wastreated with Methanol (1018 mL, 20.0 vol.), then stirred for 1 h at25±5° C., filtered, washed with Methanol (101.74 mL, 2.0 vol.) and driedunder reduced pressure at 60±5° C. for 16 h to obtain Formula-I as anoff-white solid (36.5 g, 71.75%). The solid obtained was optionallytreated with methanol (20.0 vol) at 25-30° C. and filtered. Compound wasdried under reduced pressure at 60±5° C. for 16 h to obtain crystallineanhydrous lenalidomide Form IV of Formula-I as an off white solid.

Example-2b Step-a:

To a suspension of Formula-II (100 g, 0.345 mol.) in N,N-Dimethylacetamide (500 mL, 5.0 vol.) was added 10% Pd/C (10.0 g, 0.1% w/w) intoa hydrogenator. This reaction mass was stirred at 60±5° C. under H₂atmosphere for 3 h. After completion of the reaction indicated by theHPLC, mass was cooled to 25±5° C., filtered through Celite® bed, washedwith N,N-Dimethyl acetamide (200 mL, 2.0 vol.). Filtrate was transferredinto a reactor, charcoalised and the mass was filtered through Celite®bed at 45±5° C., washed with N,N-Dimethyl acetamide (200 mL, 2.0 vol.)to obtain Formula-I in Dimethyl acetamide as a yellow colour solution.

Step-b:

Compound of Formula-I in N,N-Dimethyl acetamide (0.0194 mol, obtained asin step-a) was concentrated under reduced pressure to a transparentsyrupy mass. Formula IIIc (0.039 mol, 2.0 equiv) was added to the massand charged N,N-Dimethyl acetamide (5.0 mL, 1.0 vol). This mass wasstiffed for 6-12 h at 25-30° C., methanol (10 vol) was added, stirredfor 1 h at 25-30° C., filtered and dried at 45-50° C. under vacuum toobtain Formula-I as an off-white solid.

Example-2c Step-a:

Performed as per step-a of Example-2b.

Step-b:

A solution of Formula-I in N,N-Dimethyl acetamide (0.388 mol) was addedwith Saccharin of Formula IIIc (1.356 mol). This solution wasconcentrated under reduced pressure to a transparent syrupy mass. Thismass was added to Methanol (10.0 vol) at 25±5° C., then stirred for 1 hat 25±5° C. and filtered. It was dried under reduced pressure at 60±5°C. for 16 h to obtain Formula-I as an off-white solid.

Example-2d Step-a:

Performed as per step-A&B of Example-1a.

Step-b:

A slurry of Formula-Vc (150 g, 0.239 mol.) in N,N-Dimethyl acetamide(2.5 vol.) was heated to 55±5° C. under stirring to obtain a clearsolution. This solution was cooled to 25±5° C. It was added to Methanol(10.0 vol.), stirred for 1.5 h at 25±5° C., filtered and washed withMethanol (2.0 vol.). Compound was dried under reduced pressure at 60±5°C. for 16 h to obtain Formula-I as an off-white solid (38.50 g).

Example 3a

To a suspension of compound of Formula II (7.00 g), Water (105 mL, 15vol), Methane sulfonic acid (3.92 mL) and Pd/C (10% loading, 50% wet,0.70 g), hydrogen gas (90 psi) was purged at 25-30° C. The progress ofthe reaction was monitored by HPLC. After the completion of thereaction, the mass was filtered, washed with water (20 mL). pH of thefiltrate was adjusted to by adding triethylamine (9.0 mL). The slurryobtained was washed with water (2×35 mL) followed by the addition ofcompound of Formula IIIa (4.58 g). The mass was heated between 65 and70° C. for 5-6 h. It was cooled between 60 and 70° C., filtered anddried at 45-50° C. under reduced pressure to obtainLenalidomide-Resorcinol co-crystal of Formula Va as a crystalline solid.It was characterized by ¹H NMR, DSC, FT-IR, PXRD and TGA.

Example 3b

To a suspension of compound of Formula I (10.0 g) in water (100 mL, 10vol) was added compound of Formula IIIa (6.37 g, 1.50 equiv). Thereaction mixture was heated between 65 and 70° C. for 5 to 6 h. It wasthen filtered under hot condition and dried under vacuum at 45-50° C. toobtain Lenalidomide-Resorcinol co-crystal of Formula Va as a crystallinesolid.

Example 3c

To a suspension of compound of Formula I (1.0 g) in Ethyl acetate (10mL, 10 vol) was added compound of Formula IIIa (1.70 g, 4.0 equiv). Thereaction mixture was stirred between 25 and 30° C. for 5 to 6 h. It wasthen filtered and dried under vacuum at 45-50° C. to obtainLenalidomide-Resorcinol co-crystal of Formula Va as a crystalline solid.

Example-4

A slurry of Formula-Va (5.0 g, 0.0192 mol obtained as per the procedurementioned in Example-3a) in N,N-Dimethyl acetamide (20.0 mL, 4.0 vol.)was heated to 65±5° C. under stirring to obtain a clear solution.Solution was cooled to 25±5° C., this mass was contacted with Methanol(50.0 mL, 10.0 vol.) at 25±5° C. and filtered. Compound was dried undervacuum at 60±5° C. for 16 h to obtain Formula-I as crystalline anhydrouslenalidomide Form IV an off white solid (3.50 g, 70%).

1. A process for the preparation of crystalline anhydrous lenalidomideForm IV, comprising the following steps, (i) heating a slurry oflenalidomide co-crystal of Formula V in a suitable first solvent to asuitable temperature

 to obtain a clear solution, wherein R is a co-former selected fromResorcinol, Methyl paraben or Saccharin, (ii) cooling the reaction massto suitable temperature, (iii) mixing the reaction mass with a suitablesecond solvent, (iv) stirring at suitable temperature for a suitableperiod of time, and (v) isolating the crystalline anhydrous lenalidomideForm IV.
 2. The process for preparation of crystalline anhydrouslenalidomide Form IV of claim 1, wherein the coformer is selected fromResorcinol, Methyl paraben, or Saccharin.
 3. The process for preparationof crystalline anhydrous lenalidomide Form IV of claim 1, wherein thesuitable first solvent is selected from N,N-Dimethyl acetamide,N,N-Dimethyl formamide, N,N-Dimethyl sulfoxide, or a mixture thereof. 4.The process for preparation of crystalline anhydrous lenalidomide FormIV of claim 1, wherein the suitable temperature is selected in the rangebetween 40 and 70° C.
 5. The process for preparation of crystallineanhydrous lenalidomide Form IV of claim 1, wherein the suitable secondsolvent is selected from methanol, ethanol, propanol or a mixturethereof.